Each year in the United States, at least 1.7 million people suffer traumatic brain injury (TBI); it is a contributing factor in 33% of all injury-relate US deaths. An estimated 3.2 to 5.3 million people live with the long-term physical, cognitive, and psychological health disabilities of TBI, with annual direct and indirect costs estimated at over $80 billion. Moreover, these findings are compounded by the rapid increase in TBI cases from returning veterans of overseas deployments. It is now being recognized that TBI is a process, not an event. There is emerging evidence that this process can lead to multiple neurodegenerative disorders. Clinically, TBI is one of the most powerful environmental risk factors for the development of Alzheimer's disease and dementia. However, a molecular mechanism for this association has not been identified. Emerging evidence suggests that neuroinflammation may play a pivotal role in TBI-induced neuropathology as a result of non-specific secondary or 'bystander' injury to primarily unaffected brain regions, notably the hippocampal formation. The primary effectors of CNS neuroinflammatory response are the microglia, which act as the CNS' resident tissue macrophage. Recent work in positron emission tomography ligand imaging has shown that long-term survivors of TBI have persistent activation of this innate response for years following the initial trauma. Particularly confounding to this phenomenon is the inability to reliably distinguish resident macrophage (microglia) effects versus injury-induced infiltration of peripheral monocytes/macrophages, as upon activation, each is phenotypically indistinguishable in function and appearance. Therefore the role of these infiltrating cells in the neuropathology associated with TBI remains unclear. Aim 1: Will determine the time-related accumulation of peripherally derived CCR2 positive macrophages in the brain following TBI. Brain injury will be induced using the controlled cortical impact method on CX3CR1+/GFPCCR2+/RFP reporter mice, which allow the delineation of resident versus peripheral innate immune cells. We will examine peripheral macrophage accumulation and their inflammatory profile in the brain through a comprehensive time course spanning the acute through chronic phases following injury. Preliminary studies indicate that this model induces hippocampal-dependent cognitive dysfunction, a marked increase in CCR2 cell infiltration, as well as concomitant production of pro-inflammatory mediators. Results from this aim will examine the relationship between TBI and accumulation of peripheral macrophages and their inflammatory profile across time. Aim 2: Will determine the efficacy of targeting CCR2 pharmacologically to ameliorate TBI-induced pro- inflammatory response and ultimately cognitive dysfunction. Preliminary data suggest that targeting CCR2 positive macrophages using a novel phase-I antagonist significantly depletes peripheral macrophage accumulation following injury. Moreover, this treatment paradigm significantly decreased the expression of multiple pro-inflammatory/neurotoxic responses. As Aim will define the therapeutic basis for Aim 2, we will extend treatment paradigm to cover the peak of peripheral macrophage infiltration to examine the effects this treatment has on ameliorating TBI-induced hippocampal dependent cognitive dysfunction in the chronic phase following injury.